Apparatuses and methods as described in U.S. Pat. No. 7,339,671, entitled: “Apparatus and Method for Monitoring Biological Cell Culture”, presented a system which can perform real time and on-line monitoring of a biological cell culture in an incubator/shaker. Such system employs a light scattering technique to detect biology cell concentration (in form of turbidity or optical density) or other measurable properties of the biological culture medium in a transparent container such as an Erlenmeyer flask. With progress of wireless technologies, internet cloud and smart phone, the invention of this cell culture monitoring system initiated in a decade ago can have some new feasible improvements. When U.S. Pat. No. 7,339,671 was filed a decade ago, a practical way in term of technologies and costs for the cell culture monitoring system was to use wire to power culture detection sensor and temperature control circuit in a sensor head as well as to send measured signal or data to a control module or a computer via an intermediate control module. The sensor head is a sensing device which can be put in an incubator/shaker and can attach to a cell culture medium container in operation. However, wire connection from the sensor head to the control module can be difficult for many existing shakers because of their sealed enclosure for temperature control. Also the shaking environment can make wire connection unstable so that extra care for wire selection and wire arrangement in shakers are required. To overcome the problem of wire connection, wireless embodiment as described in the initial invention has to deal with some critical issues such as power consumption, measurement accuracy and reliable RF wireless connection. For a wireless and battery powered sensor head, the crucial challenge is to monitor biologic cell continuously and accurately for many hours or days in some case without changing or charging the battery.
With respect to the sensor head or probe defined in U.S. Pat. No. 7,339,671, the major power consumption comes from temperature control module and light sensing module. The light sensing module consists of at least one light source such as a LED or laser diode and at least one photodetector such as a photodiode. The radiation intensity of the light source and the sensitivity of the photodetector are temperature dependent. Usually incubator/shaker can operate at a temperature from ambient+5 C to 80 C. To have an accurate measurement in such temperature range, the monitoring system needs temperature control or temperature compensation for its light source and photodetector. A temperature control with peltier element dissipates a lot of electrical power and is not feasible for a battery powered sensor head. Therefore a power saving temperature compensation becomes a necessary method for constructing a wireless sensor head.
Temperature compensation methods for LED, laser diodes and photodetectors have been reported in many patent publications. Some publications such as U.S. Pat. No. 5,761,230 and U.S. Pat. No. 5,974,064 presented analog compensation circuits with temperature sensing thermistor for automatically adjusting current applied to LED and laser diode or adjusting voltage applied to photodetector. This type of temperature compensation is analog and has low power consumption. But it is not easy to find good match in temperature characteristic among thermistors and a variety of LED, laser diode or photodetector for a wide temperature range. Some publication such as EP2664264A1 and U.S. Pat. No. 5,477,576 presented software compensation with pre-measured and pre-calculated temperature coefficients of combined light source and photodetector. Because both light source and photodetector have non-linear relationship with temperature, their superimposed temperature coefficients becomes so complicated that its temperature correction could require 4th degree polynomial regression. Also for different light intensity detected in photodetector, the coefficients of polynomial are different.
In recent years, many wireless technologies (Wifi, Bluetooth, Zigbee, etc) have been used for various wireless applications. The power consumption and reliability for the wireless technologies has been improved. Bluetooth Low Energy (BLE) appears to be a technology with much low power consumption comparing with Wifi and classic Bluetooth. BLE is designed to run for months or years with a button cell battery such as CR2032. With such wireless technology, the major challenges for the wireless cell culture monitoring system are to make accurate measurement without temperature control and to prolong battery life in usage for days or weeks.
The object of this invention is to improve the cell culture monitoring system presented in U.S. Pat. No. 7,339,671 with low power consumption methods and devices. The innovated methods and devices make the cell culture monitoring system with a wireless sensor head feasible and practical. The wireless monitoring system gets rid of the wire connection problem and makes its sensor head to be easily mounted in incubator/shakers. Furthermore, the wireless monitoring system enables it to be easily integrated with not only PCs but also modern wireless devices such as smart phones and tablets.